Traditional allogeneic hematopoietic stem cell transplantation (HSCT) for treatment of patients with hematological malignancies relies on maximally tolerated doses of systemic chemoradiation to both eradicate cancer and achieve host immunosuppression. The allografts then serve to rescue patients from treatment-induced marrow aplasia and contribute a graft-versus-tumor effect of uncertain magnitude. Associated toxicities have limited HSCT to younger, medically fit patients with therapy administered on specialized hospital wards. This age restriction has excluded most patients with myeloid leukemias and B cell malignancies from transplantation. To address this limitation, we have developed a nonmyeloablative transplant approach applicable to elderly or medically infirm patients in which the burden of tumor eradication has been shifted from cytotoxic agents to the graft-versus-tumor effect. Using a large randombred canine model, we have shown that the intense conditioning regimens customarily used for host immunosuppression in HSCT could be largely replaced by optimizing postgrafting immunosuppression with a combination of mycophenolate mofetil and cyclosporine, which not only served to control serious graft-versus-host disease (GVHD) but, as importantly, reduced the magnitude of the host-versusgraft reaction. The current clinically used conditioning regimen consists of only 2 Gy of total body irradiation (TBI) and three doses of fludarabine. The preliminary clinical results have shown that this nonmyeloablative regimen was safe and minimally toxic in patients otherwise excluded from HSCT because of age or medical infirmity. In a majority of patients, transplants were carried out entirely in the outpatient setting. Importantly, impressive anti-tumor responses have been seen. Given the consistent allogeneic engraftment with minimal toxicity, we propose to extend the preliminary observations with two specific aims: 1) In patients with CML we will establish the efficacy of nonmyeloablative related HSCT for inducing long-term remissions through graftversus- leukemia effects without undue long-term complications from GVHD, and 2) we will extend the application of nonmyeloablative HSCT to include elderly recipients of unrelated grafts. We anticipate that, in later grant years, we shall carry out Phase II studies in younger patients followed by Phase III studies in which the nonmyeloablative HSCT approach is compared to standard HSCT. We anticipate that future graft-versus-tumor effects can be made more specific by the use of donor lymphocyte clones specific either for CML-specific antigens or host minor histocompatibility antigens associated with malignant cells.